The gut-skin axis in health and disease. Cath O Neill Centre for Dermatology University of Manchester

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1 The gut-skin axis in health and disease Cath O Neill Centre for Dermatology University of Manchester

2 Skin Structure Dermis Der epidermis mis subcutis Can skin structure/function be modified via the gut?

3 The gut-skin axis is not a new concept Stokes and Pillsbury 1930 A gut-brain-skin axis in Acne vulgaris. Lactobacillus acidophilus as an intervention

4 The principle players in the gut-skin axis Gut Microbiome Secretion of molecules, translocation, immune modification Diet Direct effects or via gut microbiota CNS/neuroendocrine interactions Neurohormone/neuropeptide secretion by gut/skin Metabolic interactions Circulating metabolites generated by gut/skin

5 Does the gut microbiota influence skin? Is the microbiota disturbed in skin Gut microbiota: disease? Does manipulation of the gut microbiota restore/improve skin health?

6 Is their evidence of gut dysbiosis in skin disease? Atopic Dermatitis associated with: 1. Decrease in Bifidobacteria Yes e.g. Bjorksten et al, 1999, 2000, Watanabe et al, 2003 No e.g. Kendler et al, 2006, Gore et al, Increase in E. coli and Clostridia Yes e.g. Penders et al, 2006 (KOALA study, 700 subjects) No e.g. Storro et al, Decreased bacterial diversity Yes e.g. Wang et al, 2008 No- e.g. Bisgaard et al 2011 AD is probably not all one disease

7 Severity of atopic disease inversely correlates with intestinal microbiota diversity and butyrate producing bacteria Nylund et al, 2015

8 Atopic dermatitis and sub-species level dysbiosis in Faecalibacterium prausnitzii Song et al, JACI, subjects (90 AD patients) F. prausnitzii L2-6 strain dominates. A2-165 type depleted Low butyrate and propinoate AD microbiome enriched in genes for use of nutrients released from a damaged gut

9 Psoriasis Immune and barrier disfunction Many co-morbidities (cardiovascular disease, arthritis) Increased depression and anxiety Increased suicide risk

10 Similar Depletion of Protective Faecalibacterium prausnitzii in Psoriasis and Inflammatory Bowel Disease, but not in Hidradenitis Suppurativa Epinga et al, 2016 J Crohns Colitis. 2016;10(9):

11 Does manipulation of the gut microbiota using probiotics positively affect skin disease? AD Probiotics probably don t work in established disease Overwhelming evidence for probiotics in prevention of AD 7 clinical studies e.g. Kalliomaki et al, 2003, Rautava et al, 2012 Probiotics given to mother and baby in high risk groups AD rates significantly decreased. Rautava 2012 Probiotics prevent AD if given to the mother during the last 3 months of gestation and continued on during breast feeding. Mechanism?

12 Probiotics and psoriasis 26 patient study Chronic plaque PASI<16 1X10 10 B. infantis daily for 8 weeks Groeger et al 2013

13 A role for probiotics in healthy skin?

14 The skinny, shiny, sexy mouse as an indicator of the gut skin axis Increased folliculogenesis More acidic skin Increased sebocyte production Levkovich et al. PLoS One 2013 IL-10 driven

15 Probiotics and skin -evidence in Humans? Randomised double- blind placebo- controlled study of the effects of L. paracasei ST11 Gueniche et al, 2014

16 Can probiotics be used topically?

17 Topical probiotics protect human skin form the effects of S. aureus untreated treated

18 Effects of probiotics on tight junction barrier function Tight junction Paracellular pathway O Neill and Garrod 2011

19 TEER (ohms.cm 2 ) TEER (ohms.cm 2 ) Probiotic bacteria increase tight junction function Treated Con Time (h) Time (h) LGG BL Sultanna et al, 2013

20 mean pixel intensity Lysates of probiotic bacteria increase tight junction protein expression in human skin con con BL 100 * * LGG * 50 0 Con BL LGG

21 Testing the lysate on wounded skin Excision wound

22 length of tongue (um) LGG lysate promotes re-epithelialisation in human skin D0 D1 D3 D6 LGG C 25 * * * * * * con LGG 5 0 D0 D1 D3 D7

23 Summary Many studies suggest the existence of the gut-skin axis This axis can be modified by probiotics in some instances Probiotics may have utility used topically Modulation of the gut may offer new therapeutic strategies for skin in health and disease